Neurons contact each other mostly by synaptic transmission at synapses. Synaptic transmission relies on vesicle exocytosis, i.e., fusion of vesicles with the plasma membrane and release of transmission. To maintain vesicle exocytosis, fused vesicles must be retrieved, or endocytosed, to form new vesicles for the second round of exocytosis. My goal is to improve our understanding on the cellular and molecular mechanisms underlying synaptic vesicle exocytosis and endocytosis, which are the building blocks for synaptic transmission and thus the signaling process in the neuronal network. My progress from Oct. 1, 2004 to now is listed in the following. First, we have discovered the cellular and the molecular mechanisms underlying short-term synaptic depression, a wide spread form of synaptic plasticity at synapses. We found that a decrease in the presynaptic calcium current mediated by calcium-calmodulin is the main mechanism. This finding is in contrast to the major hypothesis in the field, which is the depletion of the readily releasable pool. Our findings may overturn the long-held believe that depletion is the main cause of short-term depression. Our results are published in Neuron this year. A preview at the same issue of our publication specifically pointed out this significance. We have also submited two papers for review. In one paper, we found that calcium triggers rapid endocytosis during intensive stimulation. This finding suggests that calcium-mediated acceleration of endocytosis contributes to the maintenance of synaptic transmission during intensive nerve activity, during which fast vesicle cycling is needed to maintain synaptic transmission. In another paper, we found that quantal size, the most fundamental parameter that determines synaptic strength, is regulated by the glutamate concentration inside the vesicle. We have achieved good progress in developing a method to study the molecular mechanisms of endocytosis. The method may shed light on the molecular mechanisms underlying modulation of the kinetics of endocytosis.